Prevalence of cognitive impairment (CI) in patients with multiple sclerosis (MS): A systematic review and meta-analysis

Background: One of the complications of multiple sclerosis (MS) is cognitive impairment (CI). The prevalence of CI is reported variously in previous studies. The goal of this systematic review and meta-analysis to estimate pooled prevalence of CI in patients with MS and also the prevalence of CI based on the type of applied test. Methods: Two independent researchers systematically searched PubMed, Scopus, EMBASE, Web of Science, and google scholar as well as gray literature (conference abstracts, references of the references) which were published before up January 2022. Results: We found 4089 articles by literature search, after deleting duplicates 3174 remained. Ninety articles remained for meta-analysis. The pooled prevalence of CI using all types of tests was 41% (95% CI: 38-44%) (I2=91.7%, p<0.001). The pooled prevalence of CI using BRB test was 39% (95%CI: 36-42%) (I2=89%, p<0.001). The pooled prevalence of CI using BICAMS was 44% (95%CI: 37-51%, I2=95.4%, p<0.001). The pooled prevalence of CI using MACFIMS was 44% (95% CI: 36-53%) (I2=89.3%, p<0.001). Conclusions: The pooled prevalence of cognitive impairment in patients with MS is estimated as 41%, so CI it should be considered by clinicians.

Multiple sclerosis (MS), an autoimmune disease of central nervous system (CNS) has lots of physical and psychological complications (1,2).Cognitive impairment (CI) is one of the disabling complications of MS affecting between 40-65% of patients with MS (4).It has negative impacts on daily activities, social functioning, employment, education continuation, and finally the total quality of life (5).CI could be detected from earlier stages and progress during the time (6).CI is more prominent and more domains of cognition are affected in patients with progressive form of the disease (7).There is heterogeneity regarding degree and scope of CI in MS while the most common deficit is slowing of information processing speed and learning/memory inefficiency (8).
Different tests such as Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), Brief Repeatable Battery (BRB), minimal assessment of cognitive function in multiple sclerosis (MACFIMS) or its brief form (BICAMS) are applied for cognitive assessment in patients with MS (9).Each test evaluates different aspects of cognition and has its own advantages and disadvantages.
Up to now, lots of studies reported prevalence of cognitive impairment using different tests, but the pooled prevalence of CI based on different available tests are not present.So, we designed this systematic review and meta-analysis to estimate pooled prevalence of CI in patients with MS and also the prevalence of CI based on the type of applied test.

Methods
Study design: Systematic review, and meta-analysis.Two independent researchers systematically searched PubMed, Scopus, EMBASE, Web of Science, and Google scholar as well as gray literature (conference abstracts, references of the references) which were published before up January 2022.The search was done on January 1st 2022.
The search terns was: ("Multiple Sclerosis" OR "MS" OR "Relapsing-Remitting Multiple Sclerosis" OR "Chronic Progressive Multiple Sclerosis" OR "demyelinating diseases" OR "demyelinating disorders" OR "autoimmune demyelinating disease" AND "Cognitive Behavior Inclusion criteria were: Cross-sectional studies, and articles which had been published in the English language were included.Studies which used only one of the cognitive tests.Exclusion criteria: Clinical trials, cohorts, case-reports, letters to the editors.Two independent researchers collected data regarding first author, country of origin, number of enrolled patients, mean age, applied test for CI evaluation, F/M ratio, mean EDSS, and the number with CI.

Risk of bias assessment:
We evaluated the risk of potential bias using the Newcastle-Ottawa Scale (NOS) for Assessing the Quality adapted for cross sectional studies (10).Statistical analysis: All statistical analyses were performed using STATA (Version 14.0; Stata Corp LP, College Station, TX, USA).We used random effects model.To determine heterogeneity, Inconsistency (I2) was calculated.

Discussion
The result of this sytematic review and meta-analysis show that the pooled prevalence of CI in patients with MS is 41%, while the prevalence in included studies ranged between 14-69%.When we analyzed CI based on the applied test, the proportion of CI was higher by using MACFIMS and BICAMS (44% vs 39% by BRB).
We also found that the pooled prevalence of CI in male patients was 40% while this rate was 33% in female ones which was not correlated with demographic, psychiatric or neurologic variables.They suggested that the size or location of the lesions plays a role in CI development in men (96).They also found that memory and visuospatial construction aspects were mostly affected in men than women (96).
Beatty and Aupperle found that male patients with MS suffer more from CI than female ones and Campbell et al. enrolled 62 patients with MS using BICAMS test for cognition evaluation.They found that 65% of enrolled cases had CI which was associated with lower quality of life and unemployment.Overall, CI is common in MS and patients with progressive form of the disease suffering more from this complication.
In a cohort study, it was shown that disability status, course of the disease, and advanced age are more predictors of CI in patients with MS (97).Patients with secondary progressive form are at two fold higher risk of developing CI than RR form (12).In another study, Coric et al. enrolled 217 patients with MS and found that 44% had CI using BRB test (13).Zhang et al. applied MACFIMS test and reported CI in 14 out of 39 enrolled cases (39).
CI is common in MS and also neuromyelitis optical spectrum disorders (NMOSD).In a recent systematic review and meta-analysis, the pooled prevalence of CI in NMOSD estimated as 44% which is similar to our findings (44% vs 41%) (98).CI could have been detected in early stages of the disease or in patients with clinically isolated syndrome (CIS) which indicates that CI starts before definite diagnosis of MS (99).On the other hand, psychological problems such as depression, fatigue, and anxiety are common in MS, psychological factors could affect cognition in MS (1,100).Other factors such as disease duration, progression of the disease, and gray matter atrophy are considered as important items in developing CI (101).In a multivariate analysis, Ruano et al. investigated that advanced age and physical disability are significant predictors of CI in MS (7).
Physicians should consider CI and its evaluation in patients with MS as it has a wide range of consequences for patients.Improving psychological well-being (treating depression and anxiety), sleep quality improvement, attending cognitive rehabilitation courses, administering disease modifying therapies (DMTs) such as interferon beta (IFNb), natalizumab will impact positively on cognition status of patients with MS (102).Other strategies such as cognitive-behavioral therapy, transcranial direct current stimulation, strategy-oriented neuropsychological rehabilitation, and physical exercise training are considered as positive therapies for cognitive improvement (103).
The wide range of prevalence of CI in included studies could be due to different inclusion criteria of the patients, administration of various tests, ethnicity, and including patients with no similar clinical course.On the other hand, authors used various scoring systems (2 or 3 SD) for defining CI.This systematic review has few strengths.First, we included 90 studies.Second, we analyzed based on different applied tests.
Third, we estimated CI based on sex.It seems that the pooled prevalence of CI based on various tests ranges between 39%-44% which highlights the importance of cognitive evaluation by physicians.The pooled prevalence of cognitive impairment in patients with MS is estimated as 41%, so CI should be considered by clinicians.

Figure 1 .
Figure 1.Flow diagram summarizing the selection of eligible studies

/Country/Year Total MS Type of MS F/M MS Age(MEAN) CD diagnosis Criteria Disease duration EDSS Total CD F/M CD CD Age (MEAN)/SD Quality assessment
CD: Cognitive dysfunction, RRMS: Relapsing-remitting, SPMS: Secondary progressive MS, PPMS: Primary progressive MS, BMS: Benign MS, PRMS: Progressive relapsing MS, BRB: Brief repeatable battery, MACFIMS: Minimal assessment of cognitive function in MS, BICAMS: Brief international cognitive assessment for MS, GM: Gray matter, NS: Nonsmokers, HS: Heavy smokers, CI: Cognitive impairment, CU: Cognitive unimpairment, mCI: Mild Cognitive impairment, sCU: Sever cognitive impairment, T: Total.